Estrogen hormone action in target tissues of the body involves the interaction of the hormonal substance with a receptor protein. The specificity and responsiveness of tissues to hormonal stimulation are governed in most part by the presence and biochemical action of this receptor protein. Nuclear localization of the receptor protein and its activity was shown to be increased by exposure to growth factors. suggesting a coupling of these two signaling pathways. Gene regulation studies using mutant proteins in transfected cells show that growth factors regulate activity through the N-terminal region of the receptor while estrogen acts through the C-terminal end. Estrogen has an associated effect on bone homeostasis which has now been shown to occur through a receptor mediated mechanism, Prenatal or neonatal estrogen exposure of mice has shown for the first time a highly sensitive and significant influence on adult bone density. Bone cells have extremely low estrogen receptor levels and inconsistent response to estrogen. Estrogen was shown to specifically stimulate exogenous and endogenous genes in the cell lines. Regulation of responsiveness was shown to be influenced by cellular protein kinase C activity by decreasing receptor binding levels with no influence on the receptor gene or protein. This example of signal coupling illustrates an additional level of regulation of hormone response than previously thought. The finding also helps to explain the multi hormonal effects on bone homeostasis. Estrogen receptor is being expressed in yeast for analysis of the gene transcriptional activity of the protein using a variety of hormonally regulated promoter sequences linked to beta-galactosidase reporter genes. Site directed mutagenesis of the ligand binding domain of the receptor protein has identified specific amino acids which influence transactivation activity with no effect on ligand binding. Combined site directed and deletion mutagenesis has shown a clear interaction between the N and C terminal regions of the receptor related to its transcriptional activity. These findings have isolated a peptide region in the N terminus of the receptor which interacts with a specific amino acid in the ligand binding site. Such observations are needed in order to determine the structural conformation of the estrogen receptor related to hormone activation by a variety of estrogenic compounds to explain differential hormonal agonist activity in various estrogen target tissues.